Frailty is a complication of aging resulting from a dysregulation of multiple systems leading to increased morbidity, and ultimately increased mortality. The prevalence of frailty is 3-fold higher in human immunodeficiency virus type-1 (HIV-1) infected patients than age-matched HIV-negative controls, and occurs 20 years earlier than would be expected in HIV-1-negative aging patients. Preliminary analyses of ongoing studies of frailty by our group suggest a previously unrecognized association between immune activation, immune senescence, and clinical frailty in HIV-1-infected persons treated with highly-active antiretroviral therapy (HAART). The global aim of this proposal is to understand the mechanisms of immune dysfunction in HIV-1-infected frail individuals. To evaluate the global aim, we will use stored samples from HIV-1 infected frail individuals and matched HIV-1 infected non-frail controls to 1) Determine the role of chronic cytomegalovirus (CMV) co-infection in HIV-related frailty through CMV-antigen stimulation of T-cells 2) Investigate the role of microbial gut translocation in HIV-related frailty through plasma lipopolysaccharide (LPS) and soluble activation marker CD14 (sCD14) and 3) Use microarray analysis of human T-cell genes to identify potential gene expression patterns associated with the frail phenotype in HIV-1 infected persons. The proposed research will provide the first analysis of the role of chronic CMV infection, microbial translocation, and polymorphisms in T- cells in the development of HIV-1-related frailty. The results will have significant clinical implications in efforts to diagnose, treat, and prevent frailty in HIV-1-infected and uninfected individuals.